Ivabradine hydrochloride of formula I, has very valuable pharmacological and therapeutic properties, and is useful in many cardiovascular diseases such as angina pectoris, myocardial infarct and associated rhythm disturbances and is chemically known as (S)-7,8-dimethoxy-3-{3-{N-[(4,5-dimethoxybenzocyclobut-1-yl)methyl]-N-(methyl)amino)propyl)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one.

Ivabradine hydrochloride is first disclosed in U.S. Pat. No. 5,296,482. The disclosed process comprises the condensation of (S)—N-[(4,5-dimethoxybenzocyclobut-1-yl)-methyl]-N-(methyl)amine of Formula II,
with 7,8-dimethoxy-3-[3-iodopropyl]-1,3-dihydro-2H-3-benzazepin-2-one Formula III,
in acetone and in presence of a base such as potassium carbonate. The resulting benzazepine intermediate of formula IV is purified by column chromatography, and
is further reduced with palladium hydroxide in glacial acetic acid under the atmosphere of hydrogen gas to get ivabradine which is converted into its hydrochloride salt by the action of aqueous hydrochloric acid.
The methyl amine derivative of formula II is prepared by the reduction of 1-cyano-4,5-dimethoxybenzocyclobutane of Formula V,
with borane tetrahydrofuran complex which upon condensation with ethyl chloroformate and further reduction with lithium aluminium hydride in tetrahydrofuran resulted in racemic compound of methyl amine derivative of formula II. The racemic compound is resolved to (+) isomer of methyl amine derivative of formula II with (d)-camphorsulphonic acid.
Benzazepine derivative of formula III is prepared by the reaction of sodium iodide with 7,8-dimethoxy-3-[3-chloropropyl]-1,3-dihydro-2H-3-benzazepin-2-one of formula VI,
in acetone and the resulting iodo intermediate is purified by dissolving it in water and extraction with dichloromethane.
It has been observed that the said process suffers from many drawbacks such as the use of borane-tetrahydrofuran complex which is unstable at room temperature and purification of intermediates and ivabradine by chromatographic techniques. The chromatographic technique for purification is cumbersome, tedious and difficult to utilize on an industrial scale.
The use of aqueous hydrochloride in the preparation of ivabradine hydrochloride is also not suggested because the removal of hydrochloric acid by distillation may lead to the decomposition and results in the generation of impurities and hence further purification is required. Also, use of highly flammable and large quantities of organic solvent in the preparation of benzazepine intermediate of formula IV makes this process unattractive for large scale production.
The above mentioned drawbacks call for an alternative and improved process for the preparation of highly pure ivabradine hydrochloride that would be commercially viable, reproducible on industrial scale and meets the needs of regulatory agencies.
Subsequent U.S. Pat. No. 7,176,197 reports α crystalline form of ivabradine hydrochloride. Several other crystalline forms such as beta, gamma, delta, beta-d, gamma-d and delta-d are also reported by Les Laboratories. There is no data available in the prior art for the existence of amorphous ivabradine hydrochloride.
Crystalline solids normally require a significant amount of energy for dissolution due to their highly organized, lattice like structures. For example, the energy required for a drug molecule to escape from a crystal is more than from an amorphous or a non-crystalline form. It is known that the amorphous forms in a number of drugs exhibit different dissolution characteristics and in some cases different bioavailability patterns compared to the crystalline form (Econno T., Chem. Phazm Bull., 1990; 38: 2003-2007). For some therapeutic indications, one bioavailability pattern may be favoured over another. An amorphous form of cefuroxime axietil is an example of one amorphous drug exhibiting much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for cefuroxime axietil pharmaceutical dosage form development. Additionally, the aqueous solubility of crystalline atorvastatin calcium is lower than its amorphous form, which may result in the difference in their in vivo bioavailability. Therefore, it is desirable to have amorphous forms of drugs with high purity to meet the needs of regulatory agencies and also highly reproducible processes for their preparation.
In view of the above, it is, therefore, desirable to provide an efficient, more economical, less hazardous and eco-friendly process for the preparation of highly pure ivabradine or a pharmaceutically acceptable salt thereof where impurity formation is less and hence avoids chromatographic purification and is convenient to operate on a commercial scale. Further, an amorphous form of ivabradine hydrochloride has also been provided in the present application for which the protection is sought.